title: Pathogenicity of the novel A/H7N9 influenza virus in mice.
abstract: A novel avian-origin influenza A/H7N9 virus infecting humans was first identified in March 2013 and, as of 30 May 2013, has caused 132 human infections leading to 33 deaths. Phylogenetic studies suggest that this virus is a reassortant, with the surface hemagglutinin (HA) and neuraminidase (NA) genes being derived from duck and wild-bird viruses, respectively, while the six "internal gene segments" were derived from poultry H9N2 viruses. Here we determine the pathogenicity of a human A/Shanghai/2/2013 (Sh2/H7N9) virus in healthy adult mice in comparison with that of A/chicken/Hong Kong/HH8/2010 (ck/H9N2) virus, highly pathogenic avian influenza (HPAI) A/Hong Kong/483/1997 (483/H5N1) virus, and a duck influenza A H7N9 virus of different genetic derivation, A/duck/Jiangxi/3286/2009 (dk/H7N9). Intranasal infection of mice with Sh2/H7N9 virus doses of 10(3), 10(4), and 10(5) PFU led to significant weight loss without fatality. This virus was more pathogenic than dk/H7N9 and ck/H9N2 virus, which has six internal gene segments that are genetically similar to Sh2/H7N9. Sh2/H7N9 replicated well in the nasal cavity and lung, but there was no evidence of virus dissemination beyond the respiratory tract. Mice infected with Sh2/H7N9 produced higher levels of proinflammatory cytokines in the lung and serum than did ck/H9N2 and dk/H7N9 but lower levels than 483/H5N1. Cytokine induction was positively correlated with virus load in the lung at early stages of infection. Our results suggest that Sh2/H7N9 virus is able to replicate and cause disease in mice without prior adaptation but is less pathogenic than 483/H5N1 virus.
  
  
  OBJECTIVE
  An H7N9 virus isolate causing fatal human disease was found to be more pathogenic for mice than other avian H9N2 or H7N9 viruses but less pathogenic than the highly pathogenic avian influenza virus (HPAI) H5N1. Similarly, the ability of Sh2/H7N9 to elicit proinflammatory cytokines in the lung and serum of mice was intermediate to ck/H9N2 and dk/H7N9 on the one hand and HPAI H5N1 on the other. These findings accord with the observed epidemiology in humans, in whom, as with seasonal influenza viruses, H7N9 viruses cause severe disease predominantly in older persons while HPAI H5N1 can cause severe respiratory disease and death in children and young adults.
authors.affiliation: Centre of Influenza Research, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Chris Ka Pun
authors.initials: CK
authors.lastname: Mok
authors.forename: Horace Hok Yeung
authors.initials: HH
authors.lastname: Lee
authors.forename: Michael Chi Wai
authors.initials: MC
authors.lastname: Chan
authors.forename: Sin Fun
authors.initials: SF
authors.lastname: Sia
authors.forename: Maxime
authors.initials: M
authors.lastname: Lestra
authors.forename: John Malcolm
authors.initials: JM
authors.lastname: Nicholls
authors.forename: Huachen
authors.initials: H
authors.lastname: Zhu
authors.forename: Yi
authors.initials: Y
authors.lastname: Guan
authors.forename: Joseph Malik Sriyal
authors.initials: JM
authors.lastname: Peiris
mesh_terms: D000818:Animals; D001835:Body Weight; D002645:Chickens; D016207:Cytokines / Q000032:analysis / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D064766:Influenza A Virus, H7N9 Subtype / Q000302:isolation & purification / Q000472:pathogenicity*; D005585:Influenza in Birds / Q000821:virology; D007251:Influenza, Human / Q000821:virology; D008168:Lung / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D009296:Nasal Cavity / Q000821:virology; D009976:Orthomyxoviridae Infections / Q000473:pathology* / Q000821:virology*; D044967:Serum / Q000276:immunology; D019562:Viral Load
chemical_list: D016207:Cytokines